Thiazolo-androstanes



Cited States Patent Ofifice 3,076,801 THIAZOLO- NDROSTANES Albert Bowers and John Edwards, Mexico City, Mexico, assignors, by mesne assignments, to Syntex Corporation, a corporation of Panama No Drawing. Filed Aug. 3, 1961, Ser, No. 128,948

Claims, (Cl. 260-239.5)

exhibit anti-fibrillatory action, are represented by the.

following formula:

N W R In the above formula, R represents a hydrogen or a hydrocarbon carboxylic acyl group containing less than 12 carbon atoms; R may be hydrogen or an alkyl, alkenyl, or alkinyl group of up to 8 carbon atoms, and R represents hydrogen, lower alkyl or an aryl or aralkyl group containing less than 8 carbon atoms.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate,.

trimethylacetate, t-butylacetate, phenoxyacet-ate, cyclopentylpropionate, aminoacetate and fl-chloropropionate.

The novel compounds of the present invention are prepared by the process exemplified by the following equation:

0U BO:

N Pli III 3,076,801 Patented Feb. 5, 1-963 In the above formulas, R, R and R have the same meaning as previously set forth.

In practicing the process outlined above, the starting androstan l7 8-ol-2-one derivative (I) (obtained as described in the copending US. patent application Serial No. 128,362, filed August 1, 1961) is treated with 1.1 mol equivalents of bromine, in the presence of hydrogen bromide in a suitable solvent such as acetic acid alfording the corresponding 3p-bromo-2-ketone derivative (II).

Treatment of this derivative with a thioamide as for. example thioformarnide, thioacetamide, thiobenzamide, or phenylthioacetamide, in a suitable solvent such as ethanol, under reflux conditions for a period of time of the order of 24 hours affords the'corresponding thiazolo (4,5;2,3)- androstan-17-ol derivative.

The following. specific'examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I A solution of 3 g. of androstan-l7[3-ol-2-one in cc. of acetic acid was treated with a few drops of an acetic solution of hydrogen bromide and then dropwise and with stirring with a solution of 1.1 molar equivalents of bromine in acetic acid. When all the bromine had been consumed the reaction mixture was poured into Example I] l7a-methyl-androstan-17/3-ol-2-one, 17a-methyl-androstan-1713-o1-2-one-17-propionate and l7a-methyl-androstan-l7fl ol-2-one-l7-cyclopentylpropionate were treated following the technique described in Example I, furnishing 3/3 bromo 17a methyl androstan 17/3 o1 2 one, 3;? bromo 17a methyl androstan 17,8 ol -2 one-17-propionate, and 3B bromo-l7a-methyl-androstanl7B-ol-2-one-17-cyclopentylpropionate.

Example 111 When applying the procedure described in Example I to 17ot-Vil1Yl-3IldIOStElII-175*01-2-0116, l7a-vinyl-androstan- 17B-ol-2-one-l7-acetate, 17u-vinyl-androstan-17fi-ol-2-onel7-capr0ate, there were correspondingly obtained 3,8- bromo-17a-viny1-androstan-17fio1-2-one, 3fi-bromo-l7avinyl-androstan17fl-o1-2-one-17-acetate, and 3fl-bromo- 17a-vinyl-androstan-17,6-ol-2-one-l7-caproate.

Example 1V Using the same conditions described in Example I, there" were treated 17a-ethinyleandrostan-17,8-ol-2-one, 17a ethinyl; androstan 17,8 o1 2 one 17 pro pionate, and 17a-ethiny1-androstan-17p3-ol-2-one-17 cyclopentylpropionate, thus affording respectively 3j8-bromo- 1.7a ethinylandrostan 17H- 01 2 one, 35 bromo 17a ethinyl androstan 17B o1 2- one 17 pro pionate, and 3 B-bromo-l7a-ethinyl androstan-175-01-2- one-17-cyclopentylpropionate.

Example V A solution of 2 g. of 3p-bromo-androstan-17fl-ol-2-one and 2 g. of thioformamide in cc. of ethanol was refluxed for 24 hours. Then the greater part of the solvent was removed and water added. The resulting mixture was washed with ethyl acetate and then made Example VI There were treated by the above technique 3fi-bromo- 17a-methy1-androstan-17fi-ol-2-one, 3 .3-bromo-l7a-methyl-androstan-17;3-ol-2-one-l7-propionate, and 3p-bromo- 17a-methy1-androstan 17/3 ol-2-one-17-cyclopentylpropionate, giving respectively thiazolo (4,5;2,3)-17a-methy1-androstan-l7B-ol, thiazolo (4',5';2,3)-l7a-methy1-androstan-17,8-01-17-propionate, thiazolo (4',5';2,3)-17a-methyl-androstan-l7p-ol-17-cyclopentylpropionate.

Example VII Following the technique described in Example V were treated 35-brorno 170a vinyl-androstan-17 3-ol-one, 3,8- bromo-l7u-vinyl-androstan-1713-ol-2-one-17 acetate and 3B bromo-l7a-vinyl-androstan-17fi-ol-2-one-17-caproate, affording correspondingly thiazolo (4,5;2,3)-17a-vinylandrostan 17,8 ol; thiazolo (4',5';2,3)-17a-viny1-androstan-17 3-o1-17-acetate and thiazolo (4',5';2,3) 17a-vinylandrostan-17fi-ol-17-caproate.

Example VIII Following the technique described in Example V were treated 3 3 -bromo-17a-vinyl-androstan-17;3-ol-2-one, 3 8- bromo 17a ethinyl androstan-17fiol-2-one-17-propionate, and 3,6-bromo-17a-ethiny1-androstan-17,8-ol-2-one- 17-cyclopentylpropionate, furnishing respectively thiazolo (4',5;2,3)-l7a-ethinyl-androstan-1713-01, thiazolo (4,5'; 2,3)-17,3-ethinyl-androstan-17fl-ol-17-propionate, and thiazolo (4',5';2,3) l7a-ethinyl-androstan-17fl-ol-17-cyclopentylpropionate.

Example IX Following exactly the same techniques described in Example V except that thioformamide was substituted by thioacetamide, there were treated 3fi-bromo-androstan- 175 ol 2 one, 3/3-bromo-androstan-l7fi-ol-2-one-17- acetate and 3,3-bromo-androstan-l7fl-ol-2-one-17-benzoate, affording correspondingly 2-methyl-thiazo1o (4',5; 2,3) androstan-l7fl-ol, 2'-methy1-thiazolo (4,5';2,3)-androstan-l7 3-ol-17-acetate, and 2'-methyl-thiazolo (4,5'; 2,3 -androstan- 1718-01- 1 7-benzoate.

Example X In accordance with Example IX, there were treated 3 3- bromo 17a methyl-androstan-17fi-ol-2-one, 3B-bromo- 17a-methyl-androstan-17fi-ol-2-one 17 propionate, and 3fi-bromo 17oz methyl-androstan-l7/8-ol-2-one-17-cyclopentylpropionate, thus affording respectively 2'-methylthiazolo (4',5;2,3) 170: methyl androstan 17p ol, 2' methyl thiazolo (4',5';2,3)-17a-methyl-androstan- 17fl-ol-l7-propioinate, and 2'-methyl-thiazolo (4',5;2,3)- l7a-methyl-androstan-17,8-01-17-cyclopentylpropionatc.

Example XI Following the method of Example IX were treated 3p-bromo-17a-vinyl-androstan-17,6-ol-2-one, and BB-bromo-17a-ethinyl-androstan-l7 3-ol-2-one alfording respectively 2-methyl-thiazo1o (4',5 2,3)"17XrViI'lyl-3.IldI'OStal1- 4 1718-01 and 2-methyl-thiazolo (4',5';2,3)-17a-ethinyl-androstan-17 3-ol.

Example XII 3fl-br0mo-androstan-17fi-ol-2-0ne, 3B-bromo-androstan- 17/3-ol-2-one 17-acetate and 3fl-bromo-androstan-1718-01- 2one-17-benzoate were treated following the technique described in Example V except that thioformamide Was substituted by thiobenzamide thus affording respectively 2'-phenyl-thiazolo (4,5;2,3)-androstan-17fi-ol, 2'-phenylthiazolo (4',5';2,3)-androstan-17/3 ol 17 acetate, and 2'-phenyl-thiazolo (4',5';2,3 -andro'stan-1 7,8-01- l 7-benzoate.

Example XIII In accordance with Example XII were treated 35- bromo 17cc methyl-androstan-17/3-ol-2-one, 3fi-bromo- 17oz methyl androstan 17,8 o1 2 one-17-propionate, and 3 3-bromo 17a methyl-androstan-17/3-ol-2-one-17- cyclopentylpropionate affording correspondingly 2'-phenyl-thiazolo (4,5;2,3) 17a methyl-androstan-17fl-ol, 2 phenyl thiazolo (4',5';2,3) 17a-methyl-androstan- 17flo1-17-pr0pionate, and 2-phenyl-thiazolo (4',5';2,3)- 17a-methyl-androstan-17 8-01-17-cyclopentylpropionate.

Example XIV Following the method of Example XII, there were treated SB-bromo-17a-viny1-androstan-17fi-0l-2-one, and 3,8 bromo-17a-ethiny1-androstan-17B-ol-2-one, affording correspondingly 2-phenyl-thiazolo (4,5';2,3)-17a-viny1- androstan-17fi-ol, and 2'-pheny1-thiazo1o (4,5';2,3)-17aethinyl-androstan-175-01.

We claim:

1. A compound of the following formula:

N of? R 1W wherein R is a member of the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is selected from the group consisting of hydrogen, an alkyl group, an alkenyl group, and an alkynyl group of less than 8 carbon atoms, and R is selected from the group consisting of hydrogen, lower alkyl, an aryl group and an aralkyl group containing less than 8 carbon atoms.

2. Thiazolo(4,5';2,3)-androstan-17fi-ol.

3. Thiazolo(4,5 ';2,3 )-a1:'drostan-17 6-ol-17-acetate.

4. Thiazolo (4',5 ';2,3)-17u-methyl-androstzn-l718-01.

5. 2 methyl thiazolo(4,5;2,3) 17 methylandrostan-l7fl-ol-17 -propionate.

6. 2' phenyl thiazolo(4',5;2,3) methylandrostan-17 8-ol-17-cyclopentylpropionate.

7. Thiazolo(4',5';2,3)-17a-vinyl-androstan-175-01.

8. Thiazolo(4,5;2,3 -17a-ethinyl-androstan-175-01.

9. 2 methyl thiazolo(4',5;2,3) 17oz vinyl androstan-l7B-ol.

10. 2' phenyl thiazolo(4',5;2,3) 17oz ethinylandrostan-17fl-ol.

References Cited in the file of this patent UNITED STATES PATENTS 2,813,859 Korman Nov. 19. 1957 

1. A COMPOUND OF THE FOLLOWING FORMULA: 